Notes

Lengthy non-coding RNA FALEC encourages digestive tract cancer malignancy progression by means of regulatory miR-2116-3p-targeted PIWIL1.
In a small-scale study administering different soluble IgLONs directly into the brain and monitoring feeding, only NEGR1 altered food intake significantly. Taking NEGR1 as a prototype, our studies thus indicate that while IgLONs share a conserved mode of interaction and are able to bind each other as homomers and heteromers, they are structurally plastic and can exert unique biological action.Acute excessive ethyl alcohol (ethanol) consumption alters cardiac electrophysiology and can evoke cardiac arrhythmias, e.g., in 'holiday heart syndrome'. Ethanol acutely modulates numerous targets in cardiomyocytes, including ion channels, Ca2+-handling proteins and gap junctions. However, the mechanisms underlying ethanol-induced arrhythmogenesis remain incompletely understood and difficult to study experimentally due to the multiple electrophysiological targets involved and their potential interactions with preexisting electrophysiological or structural substrates. Here, we employed cellular- and tissue-level in-silico analyses to characterize the acute effects of ethanol on cardiac electrophysiology and arrhythmogenesis. Acute electrophysiological effects of ethanol were incorporated into human atrial and ventricular cardiomyocyte computer models reduced INa, ICa,L, Ito, IKr and IKur, dual effects on IK1 and IK,ACh (inhibition at low and augmentation at high concentrations), and increased INCX and SR Ca2+centrations promote the inducibility and maintenance of reentrant atrial and ventricular arrhythmias, supporting a role for limiting alcohol intake as part of cardiac arrhythmia management.
Rodent cardiomyocytes (CM) undergo mitotic arrest and decline of mononucleated-diploid population post-birth, which are implicated in neonatal loss of heart regenerative potential. However, the dynamics of postnatal CM maturation are largely unknown in swine, despite a similar neonatal cardiac regenerative capacity as rodents. Here, we provide a comprehensive analysis of postnatal cardiac maturation in swine, including CM cell cycling, multinucleation and hypertrophic growth, as well as non-CM cardiac factors such as extracellular matrix (ECM), immune cells, capillaries, and neurons. Our study reveals discordance in postnatal pig heart maturational events compared to rodents.

Left-ventricular myocardium from White Yorkshire-Landrace pigs at postnatal day (P)0 to 6months (6mo) was analyzed. Mature cardiac sarcomeric characteristics, such as fetal TNNI1 repression and Cx43 co-localization to cell junctions, were not evident until P30 in pigs. In CMs, appreciable binucleation is observed by P7, with extensivovascular therapies using swine, and may offer opportunities to study aspects of heart regeneration unavailable in other models.
CM maturational events such as decline of mononucleation and cell cycle arrest occur over a 2-month postnatal period in pigs, despite reported loss of heart regenerative potential by P3. Moreover, CMs grow primarily by multinucleation and longitudinal hypertrophy in older pig CMs, distinct from mice and humans. These differences are important to consider for preclinical testing of cardiovascular therapies using swine, and may offer opportunities to study aspects of heart regeneration unavailable in other models.It is a grand challenge to develop a truly effective treatment of substance use disorder (SUD), particularly for cocaine and other drugs without an FDA-approved treatment available, because a truly effective therapy must effectively block the drug's physiological and reinforcing effects during the entire period of treatment in order to achieve the long-time abstinence required by the FDA. Whether a biologic, such as monoclonal antibody, vaccine, or therapeutic enzyme, can be truly effective for SUD treatment or not has been the subject of extensive debate. The main debate question is whether a biologic, particularly an exogenous enzyme, can effectively block the drug's reinforcing effect. In this report, we demonstrate that a modest dose of a recently redesigned long-acting cocaine hydrolase, CocH3-Fc(M6), can be used to effectively block the psychostimulant, discriminative stimulus, and reinforcing effects of cocaine for a sufficiently long period of time. For example, a dose of 3 mg/kg CocH3-Fc(M6) completely blocked the discriminative stimulus and reinforcing effects for 24/25 days and continued to significantly attenuate/decrease the cocaine effects for at least 29 days in rats. All the animal data consistently suggest that the long-acting cocaine hydrolase is a truly promising candidate of enzyme therapy for treatment of cocaine use disorder.Major depressive disorder (MDD) is a severe mental disorder with a high disability rate worldwide. Selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are the most common agents for antidepressant use. SSRIs and SNRIs are believed to achieve antidepressant effects through the activation of serotonergic or noradrenergic systems. However, whether the dopaminergic system is involved remains unclear. In our study, a genetically encoded dopamine sensor and in vivo fiber photometry recordings were used to measure the dopamine concentrations in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) after acute intraperitoneal injection of SSRIs or SNRIs. Combined with the behavioral tests, we found that SNRIs increased dopamine concentrations in both the mPFC and the NAc and showed faster antidepressant effects than SSRIs. To verify the enhanced dopamine levels induce the faster antidepressant effects of SNRIs, we employed dopamine receptor antagonists to specifically block the dopaminergic function. The results showed that the faster antidepressant effects of SNRIs were weakened by the dopamine receptor antagonists. Altogether, our study reveals that SNRIs achieve faster antidepressant effects than SSRIs by elevating the dopamine concentrations in the mPFC and the NAc. Our work proposes further mechanisms for the first-line antidepressants, which provides more basis for clinical treatments. This article is part of the special issue on Stress, Addiction and Plasticity.Acute ethanol intoxication by excessive drinking is an important cause of alcohol-induced death. Stress exposure has been identified as one risk factor for alcohol abuse. Previous reports indicated that stressors may augment inhibitory effects of alcohol, but the underlying mechanism remains unknown. Here, we reported that chronic unpredictable stress increased the sensitivity to the acute ethanol intoxication in mice via impairing nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-catalase signaling. Nrf2 activity regulates the expression of catalase, a key antioxidant enzyme that mediates ethanol oxidation in the brain. Pharmacological blockade of catalase or Nrf2 activity significantly aggravated acute ethanol intoxication. Sulforaphane, a cruciferous vegetable-derived activator of Nrf2, significantly attenuated acute ethanol intoxication. Furthermore, the stress-induced aggravation of acute alcoholism was rapidly reversed by sulforaphane. Our findings suggest that Nrf2 may function as a novel drug target for the prevention of acute alcoholism, especially in psychiatric patients, by controlling catalase-mediated ethanol oxidation.
Coronavirus disease 2019 (COVID-19) has rapidly become a global pandemic. Because the severity of the disease is highly variable, predictive models to stratify patients according to their mortality risk are needed.

Our aim was to develop a model able to predict the risk of fatal outcome in patients with COVID-19 that could be used easily at the time of patients' arrival at the hospital.

We constructed a prospective cohort with 611 adult patients in whom COVID-19 was diagnosed between March 10 and April 12, 2020, in a tertiary hospital in Madrid, Spain. The analysis included 501 patients who had been discharged or had died by April 20, 2020. The capacity of several biomarkers, measured at the beginning of hospitalization, to predict mortality was assessed individually. Those biomarkers that independently contributed to improve mortality prediction were included in a multivariable risk model.

High IL-6 level, C-reactive protein level, lactate dehydrogenase (LDH) level, ferritin level, d-dimer level, neue appearance of obvious signs of clinical deterioration, and it can be used as a tool to guide clinical decision making.
The anesthetized, complete chronic atrioventricular block (CAVB) dog model allows reproducible inducibility of torsades de pointes (TdP) arrhythmias due to ventricular remodeling and after a challenge with an I
blocker. High-rate pacing (HRP) prevents ventricular arrhythmias but has long-term detrimental effects on cardiac function when applied continuously. Temporal dispersion of repolarization, quantified as short-term variability (STV), increases before ventricular arrhythmias and has been proposed as a marker to guide HRP.

The purpose of this proof-of-principle study was to show that automatically determined STV can guide HRP to prevent imminent ventricular arrhythmias.

Eight CAVB dogs were implanted with an implantable cardioverter-defibrillator (ICD) with software to automatically determine STV (STV
) in real time. During HRP, STV was measured offline from right ventricular (RV) electrograms (EGMs) and left ventricular (LV) monophasic action potential durations (MAPDs) (STV
). The CAVB dogs were challenged twice with dofetilide (0.025 mg/kg intravenously over 5 minutes or until the first TdP). In experiment 1, the individual STV
threshold before the first arrhythmic event was determined and programmed into the ICD. In experiment 2, HRP with 100 bpm was initiated automatically once the STV
threshold was reached.

In experiment 1, 8 of 8 dogs had repetitive TdP, and STV
increased from 0.96 ± 0.42 ms to 2.10 ± 1.26 ms (P <.05). In experiment 2, all dogs reached the STV threshold. HRP decreased STV
from 2.02 ± 1.12 ms to 0.78 ± 0.28 ms, which was accompanied by prevention of TdP in 7 of 8 dogs.

STV can guide HRP automatically by an ICD to prevent ventricular arrhythmias.
STV can guide HRP automatically by an ICD to prevent ventricular arrhythmias.Indirubin is a natural bis-indole alkaloid contained as active ingredient in the traditional Chinese remedy Danggui Longhui Wan. Indirubin and its 3'-oxime derivatives exhibit anti-cancer and anti-inflammatory properties and they inhibit glycogen synthase kinase (GSK)-3 in cell-free assays where 6-bromoindirubin-3'-oxime (6BIO) is among the most potent analogs. Here, we reveal 6-bromoindirubin-3'-glycerol-oxime ether (6BIGOE) as highly potent derivative able to inhibit pro-inflammatory cytokine, chemokine and prostaglandin (PG) release in human primary monocytes while increasing anti-inflammatory interleukin (IL)-10 levels. 6BIGOE suppressed lipopolysaccharide (LPS)-induced IL-1β and PGE2 release with IC50 of 0.008 and 0.02 µM, respectively, being ≥ 12-fold more potent than 6BIO. The effects of 6BIGOE are mediated via intracellular inhibition of GSK-3, where 6BIGOE again surpassed the effectiveness of 6BIO despite the higher potency of the latter in cell-free GSK-3 activity assays. Side-by-side comparison of 6BIGOE (0.1 µM) with the selective GSK-3 inhibitor SB216763 (5 µM) revealed congruent properties such as enrichment of β-catenin and suppression of cyclooxygenase (COX)-2 protein levels due to GSK-3 inhibition. Metabololipidomics using ultra-performance liquid chromatography-tandem mass spectrometry showed that 6BIGOE selectively decreases pro-inflammatory COX-derived product formation without marked modulation of other lipid mediators. In summary, 6BIGOE is a highly potent indirubin derivative in the cellular context that favorably modulates pro- and anti-inflammatory cytokines as well as COX-2-derived PG via interference with GSK-3.Snake venom three-finger α-neurotoxins (α-3FNTx) act on postsynaptic nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction (NMJ) to produce skeletal muscle paralysis. The discovery of the archetypal α-bungarotoxin (α-BgTx), almost six decades ago, exponentially expanded our knowledge of membrane receptors and ion channels. This included the localisation, isolation and characterization of the first receptor (nAChR); and by extension, the pathophysiology and pharmacology of neuromuscular transmission and associated pathologies such as myasthenia gravis, as well as our understanding of the role of α-3FNTxs in snakebite envenomation leading to novel concepts of targeted treatment. Subsequent studies on a variety of animal venoms have yielded a plethora of novel toxins that have revolutionized molecular biomedicine and advanced drug discovery from bench to bedside. This review provides an overview of nAChRs and their subtypes, classification of α-3FNTxs and the challenges of typifying an increasing arsenal of structurally and functionally unique toxins, and the three-finger protein (3FP) fold in the context of the uPAR/Ly6/CD59/snake toxin superfamily. The pharmacology of snake α-3FNTxs including their mechanisms of neuromuscular blockade, variations in reversibility of nAChR interactions, specificity for nAChR subtypes or for distinct ligand-binding interfaces within a subtype and the role of α-3FNTxs in neurotoxic envenomation are also detailed. Lastly, a reconciliation of structure-function relationships between α-3FNTx and nAChRs, derived from historical mutational and biochemical studies and emerging atomic level structures of nAChR models in complex with α-3FNTxs is discussed.On March 11, 2020, the World Health Organization (WHO) declared the severe acute respiratory syndrome caused by coronavirus 2 (SARS-CoV-2) a global pandemic. As of July 2020, SARS-CoV-2 has infected more than 14 million people and provoked more than 590,000 deaths, worldwide. From the beginning, a variety of pharmacological treatments has been empirically used to cope with the life-threatening complications associated with Corona Virus Disease 2019 (COVID-19). Thus far, only a couple of them and not consistently across reports have been shown to further decrease mortality, respect to what can be achieved with supportive care. In most cases, and due to the urgency imposed by the number and severity of the patients' clinical conditions, the choice of treatment has been limited to repurposed drugs, approved for other indications, or investigational agents used for other viral infections often rendered available on a compassionate-use basis. The rationale for drug selection was mainly, though not exclusively, based either i) on the activity against other coronaviruses or RNA viruses in order to potentially hamper viral entry and replication in the epithelial cells of the airways, and/or ii) on the ability to modulate the excessive inflammatory reaction deriving from dysregulated host immune responses against the SARS-CoV-2. In several months, an exceptionally large number of clinical trials have been designed to evaluate the safety and efficacy of anti-COVID-19 therapies in different clinical settings (treatment or pre- and post-exposure prophylaxis) and levels of disease severity, but only few of them have been completed so far. This review focuses on the molecular mechanisms of action that have provided the scientific rationale for the empirical use and evaluation in clinical trials of structurally different and often functionally unrelated drugs during the SARS-CoV-2 pandemic.The human population is burdened by morbidity and mortality from liver diseases that largely arise due to hepatitis virus infection, alcohol abuse, obesity, and diabetes. Despite 2 million global deaths per annum from liver disease, the number of drugs approved by the U.S. Food and Drug Administration (FDA) for the treatment of these disorders is sparse. Eastern medicine embodies a millennia long tradition in the use of natural product remedies for liver disease, which has attracted the interest of western medical practitioners and patients alike. Questions remain regarding the safety, efficacy, and quality of such natural products in a western medical context. Of particular concern is whether or not the mechanism of action of the product is known and, if the remedy has multiple natural constituents, how these interact at a biochemical, physiological, and clinical level. In this Commentary, we have examined the potential of metabolomics to help answer these queries, illustrated by investigations of yin chen hao tang, silymarin, and xiaozhang tie. In all cases, unique understandings of the mechanism of action of these natural products was obtained through metabolomic investigations in animal models, cell culture systems, and in clinical studies. Such mechanistic insights help assure the safety and efficacy of these natural product therapies.This study evaluated the effect of amylases on the formation, and characteristics of retrograded starches using sweet potato (SPS), cassava (CAS) and high amylose maize (HAS) starches. The starches were gelatinized, hydrolyzed with fungal or maltogenic α-amylase, de-branched and retrograded. The modified starches were then analyzed for digestibility, chain size distribution, relative crystallinity and crystallite size, thermal properties and the proportion of double helices. CAS was the most susceptible and HAS the most resistant to the action of both enzymes. Amylolysis was efficient in forming resistant starch type 3 (RS3) and high levels (> 60%) were found for all starches. RS3 content was highly correlated with the proportion of chains with degrees of polymerization between 13 and 30 for all starches, especially for the root starches, while for HAS, the high amylose content and reduction in the size of amylose chains and very long amylopectin chains also deeply contributed for the RS3 formation. These sizes (DP 13-30) are best suited for the formation of a more crystalline, more perfect, and more strongly bonded structure, composed of larger crystallites, and with a higher concentration of double helices. High correlation coefficients were found between RS3, relative crystallinity, crystallites size, and enthalpy change.The study aims to investigate the potentially neuroprotective effects and underlying mechanisms for brown seaweed polysaccharide of polymannuronic acid (PM) against Parkinson's disease (PD) pathogenesis. PD model mice were pretreated with PM via oral gavage once per day for 4 weeks and the preventative effects of PM against neuronal loss together with its modulation on brain-gut-microbiota axis were systematically explored. The results showed PM administration improved motor functions by preventing dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc) and enhanced contents of striatal homovanillic acid (HVA), serotonin (5-HT), 5-hydroxyindole acetic acid (5-HIAA) and γ-aminobutyric acid (GABA) in PD mice. PM significantly alleviated inflammation in gut, brain and systemic circulation as shown by reduced levels or expressions of pro-inflammatory cytokines concurrently and inhibited mitogen-activated protein kinases (MAPK) signaling pathway in mice colon. Meanwhile, PM greatly improved integrity of intestinal barrier and blood brain barrier (BBB) as indicated by increased expressions of tight junction associated proteins in both mice colon and SNpc. Further studies indicated PM treatment resulted in changes of gut microbial compositions, together with great alterations of digestion and metabolism of dietary proteins and fats, which led to surge increase of fecal short chain fatty acids (SCFAs) in the colon of PD mice. In conclusion, pre-administration of PM could provide neuroprotective effects against PD pathogenesis by suppressing inflammation in gut, brain and systemic circulation, and by improving integrity of intestinal barrier and BBB. PM might modulate brain-gut-microbiota axis, at least in part, via gut microbiota derived SCFAs as mediators.Protamine, a polycation, is biologically and medically relevant protein. Protamine exhibits a wide array of functions in biological processes like gene transfer, tissue and organogenesis, cell reproduction, etc. Medically, Protamine is the only clinically approved antidote for Heparin and is routinely used in various surgical interventions, and hence controlling Protamine dosing in patients is very crucial. Taking into account the medical significance of Protamine, designing simple, reliable and sensitive fluorescence sensors is highly desirable. In this work, we propose one such sensitive and reliable fluorescent sensor which is based on a template of dye-polyelectrolyte assembly constituting a molecular rotor dye, Thioflavin-T and an anionic synthetic polyelectrolyte, polystyrene sulfonate. The addition of Protamine, prompts drastic modulations in spectral features of dye-polyelectrolyte assembly which enables sensitive detection of Protamine in aqueous solution. Apart from sensitive detection, our sensing platform aids in highly selective sensing of Protamine compared to other proteins. Moreover, our sensor system is constructed on label-free, inexpensive, commercially available molecules posing as an advantage over other sensor systems which involve laborious synthesis protocols. Most importantly, our sensor template is able to sense Protamine in diluted serum sample, indicating the potential practical utility of our sensor system.We present an integrated design and fabrication strategy for the development of hierarchically structured biomechanically and biologically functional tissue scaffold. An integration of β-TCP incorporated fluffy type nanofibers and biodegradable interpenetrating gelatin-hydrogel networks (IGN) result in biomimetic tissue engineered constructs with fully tunable properties that can match specific tissue requirements. FESEM images showed that nanofibers were efficiently assembled into an orientation of IGN without disturbing its pore architecture. The pore architecture, compressive stiffness and modulus, swelling, and the biological properties of the composite constructs can be tailored by adjusting the composition of nanofiber content with respect to IGN. Experimental results of cell proliferation assay and confocal microscopy imaging showed that the as-fabricated composite constructs exhibit excellent ability for MC3T3-E1 cell proliferation, infiltration and growth. Furthermore, β-TCP incorporated functionalized nanofiber enhanced the biomimetic mineralization, cell infiltration and cell proliferation. Within two weeks of cell-seeding, the composite construct exhibited enhanced osteogenic performance (Runx2, osterix and ALP gene expression) compared to pristine IGN hydrogel scaffold. Our integrated design and fabrication approach enables the assembly of nanofiber within IGN architecture, laying the foundation for biomimetic scaffold.This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https//www.elsevier.com/about/our-business/policies/article-withdrawal.Limited studies are present on dual modification of elephant foot yam (EFY) starch and no study investigated the combined effect of citric acid (CA) and ultra-sonication (US). In the present study, EFY starch was subjected to different concentrations of CA with and without US. Changes in different properties such as functional, morphology, thermo-pasting etc. were examined. Both treatments increased the water and oil absorption capacity of starch. Pasting properties significantly (p less then 0.05) reduced with US modification, except pasting viscosity and pasting temperature. CA modification decremented the glass transition temperature which further reduced with US. Starch morphology revealed aggregation of individual granules upon CA modification whereas CA + US broke the aggregates and caused surface fissures and cracks. Overall crystallinity enhanced with an increase in the citric acid concentration. Changes in functional groups identified by FTIR analysis showed new peak formation (1710-1690 cm-1) associated with CA modification. The results showed that CA and CA + US changed the functionality, morphology and other structural characteristics of EFY starch which enable us to use the modified starch in the range of application i.e. bakery products, extruded products, thickening agent and other.
To construct tissue engineered corneal epithelium from a clinical-grade human embryonic stem cells (hESCs) and investigate the dynamic gene profile and phenotypic transition in the process of differentiation.

A stepwise protocol was applied to induce differentiation of clinical-grade hESCs Q-CTS-hESC-1 and construct tissue engineered corneal epithelium. Single cell RNA sequencing (scRNA-seq) analysis was performed to monitor gene expression and phenotypic changes at different differentiation stages. Immunostaining, real-time quantitative PCR and Western blot analysis were conducted to detect gene and protein expressions. After subcutaneous transplantation into nude mice to test the biosafety, the epithelial construct was transplanted in a rabbit corneal limbal stem cell deficiency (LSCD) model and followed up for eight weeks.

The hESCs were successfully induced into epithelial cells. scRNA-seq analysis revealed upregulation of ocular surface epithelial cell lineage related genes such as TP63, Pax6, KRT14, and activation of Wnt, Notch, Hippo, and Hedgehog signaling pathways during the differentiation process. Tissue engineered epithelial cell sheet derived from hESCs showed stratified structure and normal corneal epithelial phenotype with presence of clonogenic progenitor cells. Eight weeks after grafting the cell sheet onto the ocular surface of LSCD rabbit model, a full-thickness continuous corneal epithelium developed to fully cover the damaged areas with normal limbal and corneal epithelial phenotype.

The tissue engineered corneal epithelium generated from a clinical-grade hESCs may be feasible in the treatment of limbal stem cell deficiency.
The tissue engineered corneal epithelium generated from a clinical-grade hESCs may be feasible in the treatment of limbal stem cell deficiency.Acute lung injury is an acute inflammatory disease with high morbidity rate and high mortality rate. However, there is still no effective clinical treatment to date. Our previous studies found that NLRC5 was significantly increased in acute liver injury model induced by LPS to reduce the secretion of IL-6 and TNF-α. Nevertheless, there is no report on the role of NLRC5 in regulating the development of acute lung injury. In this study we successfully established a model of acute lung injury induced by tracheal instillation of LPS in mice, and found NLRC5 expression was apparently elevated in mouse lung tissue and primary alveolar macrophages. NLRC5 overexpression negatively regulated secretion of inflammatory cytokines in murine alveolar macrophage cells through NF-κB and p38 MAPK pathway inhibition. There is a positively feedback between NLRC5 and NF-κB or p38 MAPK pathway. This study may provide some new ideas for clinical prevention of lung injury.Exposure to air pollution is associated with the incidence of respiratory diseases. The present study evaluated the pulmonary vascular system injury by chronic real-time particulate matter (PM10) exposure and investigated the underlying mechanisms. Rats were exposed to PM10 or filtered air for 2 to 4 months using a whole body exposure system, and intraperitoneally injected with the MEK1/2 inhibitor U0126. Right heart catheterization and myography were performed to detect lung function and pulmonary vascular reactivity, respectively. Western blotting, qRT-PCR, enzyme-linked immunosorbent assay and histological analyses were used to detect the effects and mechanisms by which PM10 exposure-induced pulmonary vascular dysfunction. Functional experiment results showed that PM10 exposure increased the pulmonary artery pressure of rats and caused endothelin B receptor (ETBR)-mediated pulmonary arteriole hyperreactivity. U0126 significantly rescued these pathological changes. PM10 exposure upregulated the contractile ETBR of pulmonary arteriolar smooth muscle, and damaged pulmonary artery endothelial cells to induce the release of more endothelin 1 (ET-1). The upregulated ETBR bound to increased ET-1 induced pulmonary arteriolar hyperresponsiveness and remodeling. U0126 inhibited the PM10 exposure-induced upregulation of ETBR in pulmonary arteriole, ETBR-mediated pulmonary arterial hyperresponsiveness and vascular remodeling. In conclusion, chronic real-time particulate matter exposure can activate the ERK1/2 signaling, thereby inducing the upregulation of contractile ETBR in pulmonary arteriole, which may be involved in pulmonary arteriole hyperresponsiveness and remodeling in rats. These findings provide new mechanistic evidence of PM10 exposure-induced respiratory diseases, and a new possible target for treatment.Di (2-ethylhexyl) phthalate (DEHP) is a known environmental endocrine disruptor that impairs development of testis and spermatogenesis. This study aims to explore the effects of STAT3/p53 and PI3K-Akt-mTOR signaling pathway on DEHP-induced reproductive toxicity in pubertal male rat. 24 6-week-old male Sprague-Dawley rats were randomly divided into 4 groups (Control, low-dose, middle-dose and high-dose group) and were treated with increasing concentration of DEHP (0, 250, 500, 1000 mg/kg/day) respectively for 28 consecutive days by intragastric administration. Our results showed that DEHP exposure induced obvious morphological changes of testis, decreased organ coefficient of testis and sperm count, and increased testicular cell apoptosis in the 500 and 1000 mg/kg/day DEHP groups (p less then .05). The serum testosterone decreased in a dose-dependent manner after treatment with DEHP. Furthermore, the exposure of DEHP elevated the levels of oxidative stress accompanied by upregulated expression of p53 and reduced expression of STAT3. In addition, compared with the control group, the expression of PI3K, p-Akt and p-mTOR proteins significantly decreased, whereas the downstream autophagy-related proteins phosphorylated ULK1, Beclin-1, Atg7, LC3-II obviously increased in the 250 mg/kg/day DEHP group (p less then .05). The expression of p62 was reduced in DEHP-treated groups. Our data indicated that autophagy could be activated to protect testes from DEHP-induced reproductive damage by inhibiting PI3K-Akt-mTOR signaling pathway in the 250 mg/kg/day DEHP group. STAT3/p53-mediated mitochondrial apoptosis pathway might play a major role to cause testis injury and reproductive dysfunction in the 500 and 1000 mg/kg/day DEHP groups.Although occupational exposure to antimony and its compounds can produce pulmonary toxicity, human carcinogenic impacts have not been observed. Inhalation studies with respirable antimony trioxide particles administered to rats and mice have, however, induced carcinogenic responses in the lungs and related tissue sites. Genotoxicity studies conducted to elucidate mechanism(s) for tumor induction have produced mixed results. Antimony compounds do not induce gene mutations in bacteria or cultured mammalian cells, but chromosome aberrations and micronuclei have been observed, usually at highly cytotoxic concentrations. Indirect mechanisms of genotoxicity have been proposed to mediate these responses. In vivo genotoxicity tests have generally yielded negative results although several positive studies of marginal quality have been reported. Genotoxic effects may be related to indirect modes of action such as the generation of excessive reactive oxygen species (ROS), altered gene expression or interference with DNA repair processes. Such indirect mechanisms may exhibit dose-response thresholds. For example, interaction of ROS with in vivo antioxidant systems could yield a threshold for genotoxicity (and cancer) only at concentrations above the capacity of antioxidant defense mechanisms to control and/or eliminate damage from ROS.Human exposures to environmental metals, including uranium (U) and arsenic (As) are a global public health concern. Chronic exposures to U and As are linked to many adverse health effects including, immune suppression and autoimmunity. The gastrointestinal (GI) tract is home to many immune cells vital in the maintenance of systemic immune health. However, very little is known about the immunotoxicity of U and As at this site. The present study examined the burden of U and As exposure in the GI tract as well as the resultant immunotoxicity to intraepithelial lymphocytes (IELs) and innate immune cells of the small intestine following chronic drinking water exposures of male and female mice to U (in the form of uranyl acetate, UA) and As (in the form of sodium arsenite, As3+). Exposure to U or As3+ resulted in high levels of U or As in the GI tract of male and female mice, respectively. A reduction of small intestinal CD4+ IELs (TCRαβ+, CD8αα+) was found following As3+ exposure, whereas U produced widespread suppression of CD4- IEL subsets (TCRαβ+ and TCRγδ+). Evaluation of innate immune cell subsets in the small intestinal lamina propria revealed a decrease in mature macrophages, along with a corresponding increase in immature/proinflammatory macrophages following As3+ exposures. These data show that exposures to two prevalent environmental contaminants, U and As produce significant immunotoxicity in the GI tract. Collectively, these findings provide a critical framework for understanding the underlying immune health issues reported in human populations chronically exposed to environmental metals.Fluoxetine is one of SSRIs commonly used as first-line antidepressants. It also induces adverse effects, including bleeding events. This study clarified the bleeding effect of fluoxetine and explored the action cascade of this drug leading to a longer bleeding time. A total of 48 male adult mice were evenly distributed into four groups and given fluoxetine in saline at 0, 4, 8, or 16 mg/kg, for 14 days. On day 15, tail bleeding time of 6 mice/group was measured, and their blood samples were collected for analyses of relevant platelet functions. The remained mice were allowed to survive for another 14 days without fluoxetine, and subjected to the same analyses on day 29. A significant effect of fluoxetine was reveled on bleeding time (F (3,20) = 16.842, P less then 0.01) and intraplatelet serotonin (F (3,20) = 90.967, P less then 0.01). Moreover, fluoxetine effectively inhibited platelet aggregation (F(3, 20) = 30.247, P less then 0.01), decreased amount of GPIbα (F(3, 20) = 23.855, P less then 0.01), suppressed GPIIb/IIIa activation (F(3, 20) = 89.441, P less then 0.01), and lowered P-selectin (F(3, 20) = 7.960, P less then 0.01) on platelet surface. Negative correlations existed between bleeding time and the aforementioned four indices, whereas correlations between intraplatelet serotonin and the same indices were positive. All changes returned to same levels as Control group after fluoxetine withdrawal. These data suggest an action pathway of fluoxetine starting at binding to serotonin transporter, followed by decreased intraplatelet serotonin, increased GPIbα shedding, suppressed GPIIb/IIIa activation, and inhibited α-granule release, and concluding with prolonged bleeding time in mice.Wound repair and regeneration is a complex orchestrated process, comprising several phases interconnecting various cellular events and triggering multiple intracellular molecular pathways in damaged cells and tissues. In several metabolic disorders including diabetes mellitus, delay in wound healing due to elevated levels of cellular stress poses a key challenge. Several therapeutic wound dressing materials and strategies including hyperbaric oxygen therapy and negative pressure wound therapy have been developed to accelerate repair and restore cellular homeostasis at the wound site. Further, tremendous progress has been made in identification of transcriptional regulators involved in the process of wound healing. Nuclear factor erythroid 2-related factor 2 (Nrf2), a redox sensitive transcription factor, is the key regulator of intracellular redox homeostasis which induces the expression of cytoprotective genes and increases the production of antioxidants that scavenge free radicals. Activators of Nrf2 have been reported to combat oxidative stress and enhance the process of wound healing in several pathophysiological conditions, including diabetes and its complications such as diabetic foot ulcer, and chronic kidney disease, and diabetic nephropathy. Several bioactive compounds have been reported to reduce cellular stress, and thus accelerate cell proliferation, neovascularization results in repairing damaged tissues by the activation of the transcription factor, Nrf2. This review is focused on the strategies for diabetic wound healing and the highlights the role of bioactive compounds that activate the Nrf2 signaling and revitalize the cellular and molecular mechanism in the chronic wound niche, regulate and restore redox homeostasis thereby promoting wound repair and regeneration.Diabetic nephropathy (DN) is the major cause of end-stage renal disease. Resveratrol (RSV) has been shown to exert a renoprotective effect against DN, but despite research progress, the protective mechanisms of RSV have not been fully elucidated. Here, we demonstrated that RSV relieved a series of pathological characteristics of DN and attenuated oxidative stress and apoptosis in the renal tissues of diabetic (db/db) mice. In addition, RSV inhibited oxidative stress production and apoptosis in human podocytes exposed to high glucose. Furthermore, inhibition of reactive oxygen species generation by reactive oxygen species scavengers N-acetylcysteine and 2,2,6,6-tetramethyl-1-piperidinyloxy had the same anti-apoptosis effects on podocytes as did RSV. Finally, we found that 5' adenosine monophosphate-activated protein kinase (AMPK) was activated by RSV in db/db mice and podocytes exposed to high glucose. The protective effects of RSV on podocytes were suppressed by Compound C, a pharmacological inhibitor of AMPK. Together, our results indicate that RSV effectively attenuated renal damage by suppressing oxidative stress-mediated apoptosis of podocytes, which was dependent on AMPK activation. This study revealed a possible mechanism to protect podocytes against apoptosis in DN.Recently, it has reported that many inflammatory bowel disease (IBD) patients were contracted secondary liver injury. Monotropein (MON), an iridoid glycoside, is demonstrated to possess protective effects on acute colitis mice due to its anti-inflammatory activities. However, it was remained unknown whether MON could inhibit secondary liver injury caused by IBD. The aim of the present study was to investigate the protective roles and mechanisms of MON on secondary liver injury in chronic colitis mice model. In this study, 2% Dextran sodium sulfate (DSS) was used to induce mice model of chronic colitis. The results showed that MON attenuated DSS-induced hepatic pathological damage, liver parameters, infiltration of macrophages and cytokines levels. Furthermore, we found that MON attenuated liver injury through suppressing the activation of the toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling pathway and down-regulating the activity of NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome. All the data indicated that MON may be an effective therapeutic reagent to attenuate secondary liver injury induced by chronic colitis.The slowly and rapidly activating delayed rectifier K+ channels (IKs and IKr, respectively) contribute to the repolarization of ventricular action potential in human heart and thereby determine QT interval on an electrocardiogram. Loss-of-function mutations in genes encoding IKs and IKr cause type 1 and type 2 long QT syndrome (LQT1 and LQT2, respectively), accompanied by a high risk of malignant ventricular arrhythmias and sudden cardiac death. This study was designed to investigate which cardiac electrophysiological conditions exaggerate QT-prolonging and arrhythmogenic effects of sevoflurane. We used the O'Hara-Rudy dynamic model to reconstruct human ventricular action potential and a pseudo-electrocardiogram, and simulated LQT1 and LQT2 phenotypes by decreasing conductances of IKs and IKr, respectively. Sevoflurane, but not propofol, prolonged ventricular action potential duration and QT interval in wild-type, LQT1 and LQT2 models. The QT-prolonging effect of sevoflurane was more profound in LQT2 than in wild-type and LQT1 models. The potent inhibitory effect of sevoflurane on IKs was primarily responsible for its QT-prolonging effect. In LQT2 model, IKs was considerably enhanced during excessive prolongation of ventricular action potential duration by reduction of IKr and relative contribution of IKs to ventricular repolarization was markedly elevated, which appears to underlie more pronounced QT-prolonging effect of sevoflurane in LQT2 model, compared with wild-type and LQT1 models. This simulation study clearly elucidates the electrophysiological basis underlying the difference in QT-prolonging effect of sevoflurane among wild-type, LQT1 and LQT2 models, and may provide important information for developing anesthetic strategies for patients with long QT syndrome in clinical settings.
Sepsis is a life-threatening organ dysfunction syndrome arising from uncontrolled inflammatory responses. Liver injury is a crucial factor for the prognosis of sepsis. Camptothecins (CPTs) have been reported to suppress the inflammatory response induced by sepsis. G2, a CPT-bile acid conjugate, has been demonstrated the property of liver targeting in our previous research. This study aimed to research the effects of G2 on liver injury induced by cecal ligation and puncture (CLP).

C57BL/6 mice were subjected to CLP surgery, and effects of G2 on liver damage and survival rates of CLP-induced mice were evaluated. To detect the related markers of hepatic injury or neutrophil infiltration, inflammatory cytokines and protein levels, hematoxylin-eosin staining assay, corresponding Detection Kits assay, ELISA and Western blot analysis were performed.

Intraperitoneal administration of G2 reduced liver injury and enhanced the survival rates in mice with sepsis. Treatment with G2 decreased the levels of hepatic injury markers aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the serum of mice induced by CLP. The hepatic level of neutrophil infiltration marker myeloperoxidase (MPO) was reduced in G2 administration group. And the levels of serum inflammatory cytokines, including Tumor Necrosis Factor-α (TNFα), Interleukin-6 (IL-6) and IL-1β, were decreased by G2. Furthermore, the results of Western blot analysis indicated that G2 suppressed the up-regulation of NF-κB p-P65 and p-IκBα. It suggested that G2 suppressed the activation of NF-κB signaling pathway.

G2 alleviated sepsis-induced liver injury via inhibiting the NF-κB signaling pathway.
G2 alleviated sepsis-induced liver injury via inhibiting the NF-κB signaling pathway.
Arsenic, an environmental contaminant, represents a public health problem worldwide. Studies have shown its association with molecular mechanisms related to cardiomyocytes redox balance. However, the microstructure and ultrastructure of cardiac tissue, as well as the activity of its antioxidant defenses front of disturbances in the mineral bioavailability induced by arsenic are still scarce. Thus, the aim of this study was to evaluate if arsenic exposure might induce structural and ultrastructural damages in cardiac tissue, including pathological remodeling of the parenchyma and stroma. Moreover, its impact on micromineral distribution and antioxidant enzymes activity in heart tissue was also evaluated.

Adult male Wistar rats were divided into three groups that received 0, 1 and 10mg/L sodium arsenite in drinking water for eight weeks. The hearts were collected and subjected to structural and ultrastructural analysis, mineral microanalysis and antioxidant enzymes quantification. Functional markers of cardiac damages were evaluated using serum samples.

Arsenic exposure induced dose-dependent structural and ultrastructural remodeling of cardiac tissue, with parenchyma loss, increase of stroma components, collagen deposition, and pathological damages such as inflammation, sarcomere disorganization, mitochondria degeneration and myofilament dissociation. Moreover, this metalloid was bioaccumulated in the tissue affecting its micromineral content, which resulted in antioxidant imbalance and increased levels of oxidative stress and cardiac markers.

Taken together, our findings indicate that the heart is a potential target to arsenic toxicity, and long-term exposure to this metalloid must be avoided, once it might induce several cardiac tissue pathologies.
Taken together, our findings indicate that the heart is a potential target to arsenic toxicity, and long-term exposure to this metalloid must be avoided, once it might induce several cardiac tissue pathologies.
ATP-binding cassette (ABC) transporters constitute one of the largest families of membrane proteins in most organisms; however, their functions in hepatocellular carcinoma (HCC) remain unclear.

A set of bioinformatic tools was integrated to analyze the expression of 49 members of the ABC transporter family. The function of members which had prognostic values in HCC was explored by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis.

ABCA8 and ABCA9 were significantly down-regulated in HCC. Prognostic analysis indicated that HCC patients with low expression of ABCA8 and ABCA9 had significantly shorter survival time. On the contrary, ABCB6 was over-expressed in the disease and high expression of ABCB6 was associated with worse prognosis. Co-expression analysis, and subsequently GO and KEGG analysis indicated that ABCA8 and ABCA9 might participate in the catabolic processes of multiple metabolites, while ABCB6 might regulate ferroptosis.

This study reveals a previously unrecognized function of ABCB6 in HCC, by regulating ferroptosis. Since ABCB6 is over-expressed in HCC and ferroptosis involves in cancer development, ABCB6 might be a promising therapeutic target in the disease.
This study reveals a previously unrecognized function of ABCB6 in HCC, by regulating ferroptosis. Since ABCB6 is over-expressed in HCC and ferroptosis involves in cancer development, ABCB6 might be a promising therapeutic target in the disease.Although breast cancer is one of the leading troublesome cancers, the available therapeutic options have not fulfilled the desired outcomes. Immune-based therapy has gained special attention for breast cancer treatment. Although this approach is highly tolerable, its low response rate has rendered it as an undesirable approach. This review aims to describe the essential oncogenic pathways involved in breast cancer, elucidate the immunosuppression and oncogenic effect of Mucin1, and introduce myeloid-derived suppressor cells, which are the main culprits of anti-tumoral immune response attenuation. The various auto-inductive loops between Mucin1 and myeloid-derived suppressor cells are focal in the suppression of anti-tumoral immune responses in patients with breast cancer. These cross-talks between the Mucin1 and myeloid-derived suppressor cells can be the underlying causes of immunotherapy's impotence for patients with breast cancer. This approach can pave the road for the development of a potent vaccine for patients with breast cancer and is translated into clinical settings.
MiR-135b is a downstream effector of oncogenic signaling pathways. This study aimed to reveal the underlying regulation and significance of miR-135b in gastric cancer.

The influence of Wnt and PI3K/AKT signaling pathways on the transcriptional activation of the miR-135b promoter was determined by dual-luciferase reporter assays. In vitro experiments, including the cell counting kit-8 (CCK8) assay, 5-ethynyl-2'-deoxyuridine (EdU) staining, flow cytometry analysis and malignant phenotype profiles, were conducted to determine the oncogenic role of miR-135b in gastric cancer. To analyze the clinical significance of miR-135b in gastric cancer, the expression profile of miR-135b in tissue specimens and plasma was examined by quantitative real-time PCR (qRT-PCR).

Oncogenic signaling pathways represented by Wnt and PI3K/AKT promoted the transcriptional activation of the miR-135b promoter in gastric cancer. Downregulation of miR-135b inhibited proliferation, promoted apoptosis, and suppressed the migratory, invagastric cancer.Malignant mesothelioma (MM) is a cancer of the mesothelial lining of the pleura, peritoneum, pericardium and testes. The most common form is asbestos-linked MM that is etiologically linked to repeated asbestos exposure with a long latency period, although non-asbestos MM has also been reported. Late diagnosis, poor survival rates, lack of diagnostic and prognostic markers act as major impediments in the clinical management of MM. Despite advances in immune checkpoint inhibition and CAR T-cell-based therapies, MM which is of different histologic subtypes remains challenging to treat. We review microRNAs (miRNAs) and the miRNA interactome implicated in MM which can be useful as circulating miRNA biomarkers for early diagnosis of MM and as biomarkers for prognostication in MM. Further, we underscore the relevance of the NRF2/MAPK signal transduction pathway that has been implicated in MM which may be useful as druggable targets or as biomarkers of predictive response. In addition, since MM is driven partly by inflammation, we elucidate chemopreventive phytochemicals that are beneficial in MM, either via crosstalk with the NRF2/MAPK pathway or via concerted anticancer mechanisms, and may be of benefit as adjuvants in chemotherapy. Taken together, a multifactorial approach comprising identification of miRNA target hubs and NRF2/MAPK biomarkers along with appropriately designed clinical trials may enable early detection and faster intervention in MM translating into better patient outcomes for this aggressive cancer.Circular RNAs (circRNAs) are a class of single-stranded RNAs having a covalently closed loop structure generated from back-splicing of pre-mRNA. These novel RNAs are characterized by high stability, abundance and conservation. Accumulating evidence has revealed that circRNAs are intimately associated with the pathogenesis, development and progression of multiple human diseases, including respiratory tract cancers. CircRNAs may serve as oncogenes or tumor suppressors to influence cell proliferation, differentiation, apoptosis, invasion and metastasis. CircRNAs may act as microRNA (miRNA) sponges, interact with RNA-binding proteins (RBPs), regulate gene transcription and/or translate into mini-peptides or proteins. In this review, we discuss recent progress in understanding the pathologic roles of circRNAs in respiratory tract cancers, such as nasopharyngeal carcinoma, laryngeal squamous cell carcinoma, and especially lung adenocarcinoma. We further discuss the diagnostic, therapeutic and prognostic roles as potential biomarkers in respiratory tract cancers, providing insight into the possibilities of applying circRNAs as therapeutic targets and biomarkers in precision oncology.
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